Type 2 diabetes is a growing health problem. Major precursors to diabetes include obesity and genetic susceptibility. The at-risk for diabetes phenotype ("prediabetes") has been characterized by clinical research studies but needs better characterization in health care systems that serve as the major locus for prevention and treatment. This is a mid-career investigator award in patient-oriented research (K24) proposal. The candidate, James B. Meigs MD MPH, has devoted his patient-oriented research career to study of the etiology and prevention of type 2 diabetes. This award will support the following broad Specific Aims: 1. Elucidate the roles of obesity and genetic risk in the pathogenesis of type 2 diabetes by tests of hypotheses that a) adipokine dysregulation is the link whereby obesity causes type 2 diabetes;b) arrayed and specific candidate single nucleotide polymorphisms (SNPs) are associated with type 2 diabetes and related quantitative traits; 2. Translate epidemiological knowledge of the prediabetes phenotype into clinical application for population health benefit by tests of hypotheses that a) prediabetes defined by surrogate markers available in the electronic health record (EHR) has a phenotype whose metabolic profile is similar to that of prediabetes defined rigorously in clinical and epidemiologic studies;b) people with "EHR prediabetes" have health care utilization and clinical outcomes intermediate between those without EHR prediabetes and those with clinical diabetes, suggesting value in identifying such people for intervention to reduce risk; 3. Build on the candidate's successful research and mentoring program by ensuring mid-career protected time for a) patient-oriented research program development within the superb environment of Harvard, Massachusetts General Hospital and an extensive network of research collaborations;b) expanded capacity to provide a greater depth of mentoring to a larger number of patient-oriented research junior investigators. Patient-oriented research is critical to the translation of scientific knowledge into population health benefit. Type 2 diabetes is a rapidly growing clinical and public health problem. This mid-career award application seeks directly to address the need for patient-oriented research and mentoring focused on the causes and consequences of type 2 diabetes. Expanded knowledge of precursors of type 2 diabetes is critical to identify novel approaches for prevention and control of the widening diabetes epidemic.